Augmentation of the endogenous pulmonary innate immune defenses is an ideal broad spectrum, first response strategy for an aerosolized microbial biothreat. In this proposal, we preseiit evidence that keratinocj^e growth factor (KGF), an epithelial mitogen, enhances both the soluble and cellular defenses in the alveolar lining fluid. Within an hour of KGF administration, the pulmonary epithelium releases cytokines and chemokines including GM-CSF, which primes macrophage phagocytic and oxidant functions through activation of the stat signaling cascade. In addition, KGF results in alveolar tj^e II cell hyperplasia, and upregulates the expression of the pulmonary collectins, surfactant proteins A and D. Preliminary data presented in this proposal indicates that pretreatment of mice with KGF enhances the neutralization of influenza virus by alveolar lining fluid, and accelerates the clearance of gram positive, gram negative and fungal organisms from the lungs of mice. These actions are mediated in part by the pulmonary collectins which promote the aggregation, permeabilization and opsonization of organisms which are deposited at the air-liquid interface. In the first aim, we will test the hypothesis that KGF augments the innate immune defenses of the alveolar epithelium by induction of the collectins and antimicrobial peptides. The hypothesis to be tested in the second aim is that KGF augments the innate immune defenses of the alveolar epithelium by activation and recruitment of phagocytes to the airspace, through cytokine and collectin dependent mechanisms. The third aim will explore the collectin dependent and independent mechanisms of in vivo clearance of influenza A virus and several Gram negative pathogens, including Francisella novicida. The overall objective of this project is to determine if augmentation of the collectin dependent and collectin independent defenses at air liquid interface of the lung can erihance the clearance of pulmonary pathogens. The collaborative applications of crystallographic structural analysis (Drs. Seaton and Head), mutagenesis, powerfitl biophysical approaches (Dr. Mendelsohn), broad expertise in collectin/IAV (Dr. Hartshorn) and collectin/LPS biology (Dr. Crouch) will provide unparalleled opprotunities to